ABSTRACT The Chemistry Core (Core C) provides enabling technology vital to the UCSF Cystic Fibrosis Research and Translation Core Center. The objective of this Center is to discover and evaluate novel small-molecule therapies for cystic fibrosis (CF), and the Chemistry Core will figure prominently in this effort by performing targeted and small molecule library synthesis. Chemistry Core interactions with investigators in the Center are categorized by three levels of service. The first level involves lead optimization and exploration of structure? activity relationships (SAR) by exhaustive synthesis, as has been done in the current award for F508del-CFTR correctors and potentiators. When possible, this will be guided by computational modeling (docking and molecular dynamics simulation). This level of participation is anticipated for co-potentiators for hard-to-treat CFTR mutations, SLC26A3 inhibitors, SLC26A4 inhibitors, TMEM16A modulators, CaCC activators, and Depending on High-Throughput Screening (HTS) Core discovery progress, as well as the importance of focused chemistry in meeting Center goals, this level of involvement may also be warranted for additional projects. Re-synthesis of lead compounds, provision of medicinal chemistry advice, and SAR analysis is the second level of Core C involvement in the Center, and many projects will benefit from this level of service. The last level of service consists of providing compounds that have already been synthesized (including modulators of hard-to-treat CFTR mutants and SLC26A gene family members) as well as providing advice on the medicinal chemistry of active compounds. The Chemistry Core will also work closely with the HTS Core to verify the identity of hits and validate hit activity by hit re-synthesis and spectroscopic characterization. All lead compounds supplied by the Chemistry Core for project and Core activities will be highly purified (generally at ~95%).